Investigation On Hydroxycamptothecin Loaded Acid-labile Polymeric Nanoparticles

Hydroxycamptothecin (HCPT) has wide antitumor spectrum, but it is insoluble in both water and physiological acceptable organic solvents and tends to change into inactive carboxylate form, which restricted the clinical application. Currently, systematical administration of the antineoplasma agent is one of the main strategies for chemotherapy. But it can be hardly delivered to target region, leading to strong side effects and low compliance and therapeutic efficacy. Acid-labile polymers have been developed as carriers of anticancer drugs through the utilization of the pH differences between the tumor and the normal tissues. There are various receptors on the surface of macrophages. and the galactosylation shows the potential strategy for hepatic cells targeting. Acid-labile nanospheres with galactose groups were proposed to target delivery of HCPT to hepatocarcinoma, thereby enhancing the availability of drug material and inhibiting effect on tumor growth.Electrosprayed nanoparticles is a novel processing technique for the production of polymer nanoparticles with diameter of hundreds nanometers and tens micrometers from electrically charged liquid jets of polymer solutions or melts under static electric field. Orthogonal experimental method was firstly used to investigate process parameters of the electrospraying system. Results of statistical analysis showed that significant influences were observed for polymer solution concentration, jet speed and needle size on nanoparticle size and encapsulation efficiency of anti-cancer drugs. Validation test showed that the experimental values of nanoparticle size and encapsulation efficiency of anti-cancer drugs were in good agreement with the calculated ones. Poly(DL-lactide)-poly(ethylene glycol) (PELA), acetal groups containing PELA (PBELA) and galactose modified PBELA (PGBELA) were introduced as nanosphere carriers for HCPT by electrospraying method. Based on the optimized process parameters. HCPT encapsulated nanospheres possessed uniformly spherical and smooth features with the average size of around 250 nm. The loading efficiency of HCPT in nanospheres was about 1.5%, and up to 50% of loading efficiency was detected.HCPT loaded PELA, PBELA and PGBELA microspheres were incubated in buffer solution of pH 7.4, pH 6.0 and pH 5.0, and the matrix degradation and drug release profiles were investigated. HCPT loaded PELA microspheres showed similar profiles of matrix degradation and drug release in the different buffer solutions, which were significantly enhanced for HCPT loaded PBELA and PGBELA microspheres after incubated in pH 6.0 and pH 5.0 buffer solutions. In vitro cell experiments indicated that polymer nanospheres without HCPT had no significant influence on cell viability, while HCPT-loaded nanospheres exhibited significant cytotoxicity. Compared with PELA and PBELA nanospheres, the cellular uptake efficiency of HepG2 cells for PGBELA nanospheres was significantly greater. In vivo study was performed through intra-tumor injection of HCPT-loaded nanospheres with respect to the tumor growth rate, animal survival rate and histological observation. all the drug treatment groups showed significant inhibition of tumor growth, and HCPT-loaded nanoparticles groups indicated the most remarkable inhibition effect.